Novel use of peptide class of compound for treating non neuropathic inflammatory pain

ABSTRACT

The present invention concerns the use of compounds of the Formula (I) for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain in mammals. The pain to be treated may be e.g. chronic inflammatory pain, rheumatoid arthritis pain and/or secondary inflammatory osteoarthritic pain. The compounds show an antinociceptive profile and differ from classical analgesics like opioids and non-steroidal anti-inflammatory drugs (NSAIDS) and are useful as specific analgesics.

FIELD OF THE INVENTION

[0001] The present invention is directed to the novel use of a peptideclass of compound for treating different types and symptoms of acute andchronic pain, especially non neurophathic inflammatory pain.

BACKGROUND OF THE INVENTION

[0002] Certain peptides are known to exhibit central nervous system(CNS) activity and are useful in the treatment of epilepsy and other CNSdisorders. These peptides which are described in the U.S. Pat. No.5,378,729 have the Formula (I):

[0003] wherein

[0004] R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group;

[0005] R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryllower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted orsubstituted with an electron donating group or an electron withdrawinggroup; and

[0006] R₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl,lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic loweralkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyllower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted orsubstituted with at least one electron withdrawing group or electrondonating group;

[0007] Z is O, S, S(O)₂, NR₄, PR₄ or a chemical bond;

[0008] Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl,and Y may be unsubstituted or substituted with an electron donatinggroup or an electron withdrawing group, provided that when Y is halo, Zis a chemical bond, or

[0009] ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,SNR₄R₇, NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

[0010] R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryllower alkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ maybe unsubstituted or substituted with an electron withdrawing group or anelectron donating group; and

[0011] R₇ is R₆ or COOR₈ or COR₈;

[0012] R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the arylor alkyl group may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and

[0013] n is 1-4; and

[0014] a is 1-3.

[0015] U.S. Pat. No. 5,773,475 also discloses additional compoundsuseful for treating CNS disorders. These compounds areN-benzyl-2-amino-3-methoxy-propionamide having the Formula (II):

[0016] wherein

[0017] Ar is aryl which is unsubstituted or substituted with halo; R₃ islower alkoxy; and R₁ is lower alkyl especially methyl.

[0018] The patents are hereby incorporated by reference. However neitherof these patents describe the use of these compounds as specificanalgesics for the treatment of acute and chronic pain, especiallyrheumatic inflammatory pain. Particularly the antinociceptive profileand properties of this class of compounds are not disclosed.

SUMMARY OF THE INVENTION

[0019] Accordingly, the present invention relates to the novel use of acompound having Formula (I) and/or Formula (II) showing antinociceptiveproperties for treating different types and symptoms of acute andchronic pain, especially non neuropathic inflammatory pain.

[0020] Particularly the present invention concerns the use of saidcompounds of Formulae (I) and/or (II) for the preparation of apharmaceutical composition for the treatment of different types andsymptoms of acute and chronic pain, especially non neuropathicinflammatory pain. This include chronic inflammatory pain e.g.rheumatoid arthritis pain and/or secondary inflammatory osteoarthriticpain.

[0021] A compound according to the invention has the general Formula (I)

[0022] wherein

[0023] R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup, or electron donating group;

[0024] R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryllower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted orsubstituted with an electron donating group or an electron withdrawinggroup;

[0025] and

[0026] R₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl,lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic loweralkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyllower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted orsubstituted with at least one electron withdrawing group or electrondonating group;

[0027] Z is O, S, S(O)₂, NR₄, PR₄ or a chemical bond;

[0028] Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl,lower alkyl, and Y may be unsubstituted or substituted with an electrondonating group or an electron withdrawing group, provided that when Y ishalo, Z is a chemical bond, or

[0029] ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅,SNR₄R₇, NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

[0030] R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryllower alkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ maybe unsubstituted or substituted with an electron withdrawing group or anelectron donating group;

[0031] R₇ is independently R₆ or COOR₈ or COR₈;

[0032] R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the arylor alkyl group may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; and

[0033] n is 1-4; and

[0034] a is 1-3.

[0035] Furthermore a compound according to the invention has the generalFormula (II)

[0036] wherein

[0037] Ar is aryl which is unsubstituted or substituted with halo; R₃ islower alkoxy; and R₁ is lower alkyl, especially methyl.

[0038] The present invention is also directed to the preparation ofpharmaceutical compositions comprising a compound according to Formula(I) and/or Formula (II) useful for the treatment of rheumaticinflammatory pain.

DETAILED DESCRIPTION OF THE INVENTION

[0039] As indicated hereinabove, the compounds of Formula I are usefulfor treating pain, particularly non neuropathic inflammatory pain. Thistype of pain includes chronic inflammatory pain e.g. rheumatoidarthritis pain and/or secondary inflammatory osteoarthritic pain. Theyshow an anti-nociceptive effectiveness.

[0040] These compounds are described in U.S. Pat. No. 5,378,729, thecontents of which are incorporated by reference.

[0041] As defined herein, the “alkyl” groups when used alone or incombination with other groups, are lower alkyl containing from 1 to 6carbon atoms and may be straight chain or branched. These groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl,hexyl, and the like.

[0042] The “aryl lower alkyl” groups include, for example, benzyl,phenethyl, phenpropyl, phenisopropyl, phenbutyl, diphenylmethyl,1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

[0043] The term “aryl”, when used alone or in combination, refers to anaromatic group which contains from 6 up to 18 ring carbon atoms and upto a total of 25 carbon atoms and includes the polynuclear aromatics.These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclicand are fused rings. A polynuclear aromatic compound as used herein, ismeant to encompass bicyclic and tricyclic fused aromatic ring systemscontaining from 10-18 ring carbon atoms and up to a total of 25 carbonatoms. The aryl group includes phenyl, and the polynuclear aromaticse.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Thearyl group also includes groups like ferrocyenyl. “Lower alkenyl” is analkenyl group containing from 2 to 6 carbon atoms and at least onedouble bond.

[0044] These groups may be straight chained or branched and may be inthe Z or E form. Such groups include vinyl, propenyl, 1-butenyl,isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl,(Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1,3 or 2,4-pentadienyl, and the like.

[0045] The term lower “alkynyl” is an alkynyl group containing 2 to 6carbon atoms and may be straight chained as well as branched. Itincludes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl,1-pentynyl, 2-pentynyl, 3-methyl-i-pentynyl, 3-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl and the like.

[0046] The term lower “cycloalkyl” when used alone or in combination isa cycloalkyl group containing from 3 to 18 ring carbon atoms and up to atotal of 25 carbon atoms. The cycloalkyl groups may be monocyclic,bicyclic, tricyclic, or polycyclic and the rings are fused. Thecycloalkyl may be completely saturated or partially saturated. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl,adamantyl, and the like. Cycloalkyl includes the cis or trans forms.Furthermore, the substituents may either be in endo or exo positions inthe bridged bicyclic systems.

[0047] The term “electron-withdrawing and electron donating” refer tothe ability of a substituent to withdraw or donate electrons,respectively, relative to that of hydrogen if the hydrogen atom occupiedthe same position in the molecule. These terms are well understood byone skilled in the art and are discussed in Advanced Organic Chemistry,by J. March, John Wiley and Sons, New York, N.Y., pp.16-18 (1985) andthe discussion therein is incorporated herein by reference. Electronwithdrawing groups include halo, including bromo, fluoro, chloro, iodoand the like; nitro, carboxy, lower alkenyl, lower alkynyl, formyl,carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl loweraklyanoyl, carbalkoxy and the like. Electron donating groups includesuch groups as hydroxy, lower alkoxy, including methoxy, ethoxy and thelike; lower alkyl, such as methyl, ethyl, and the like; amino, loweralkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto,lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) andthe like. One of ordinary skill in the art will appreciate that some ofthe aforesaid substituents may be considered to be electron donating orelectron withdrawing under different chemical conditions. Moreover, thepresent invention contemplates any combination of substituents selectedfrom the above-identified groups.

[0048] The term “halo” includes fluoro, chloro, bromo, iodo and thelike.

[0049] The term “acyl” includes lower alkanoyl.

[0050] As employed herein, the heterocyclic substituent contains atleast one sulfur, nitrogen or oxygen ring atom, but also may include oneor several of said atoms in the ring. The heterocyclic substituentscontemplated by the present invention include heteroaromatics andsaturated and partially saturated heterocyclic compounds. Theseheterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic andare fused rings. They may contain up to 18 ring atoms and up to a totalof 17 ring carbon atoms and a total of up to 25 carbon atoms. Theheterocyclics are also intended to include the so-calledbenzoheterocyclics. Representative heterocyclicx include furyl, thienyl,pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl,triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl,morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl,indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl,furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl,pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxidesof the nitrogen containing heterocycles, such as the nitric oxides ofpyridyl, pyrazinyl, and pyrimidinyl and the like. The preferredheterocyclic are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl,indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl, imidazolyl,pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a 5 or6-membered heterocyclic compound. The especially preferred heterocyclicis furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl.The most preferred heterocyclics are furyl and pyridyl.

[0051] The preferred compounds are those wherein n is 1, but di, tri andtetrapeptides are also contemplated to be within the scope of theclaims.

[0052] The preferred values of R is aryl lower alkyl, especially benzylespecially those wherein the phenyl ring thereof is unsubstituted orsubstituted with electron donating groups or electron withdrawinggroups, such as halo (e.g., F).

[0053] The preferred R₁ is H or lower alkyl. The most preferred R₁ groupis methyl.

[0054] The most preferred electron donating substituents and electronwithdrawing substituents are halo, nitro, alkanoyl, formyl,arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano,sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, loweralkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, loweralkyl, amino, lower alkylamino, di(loweralkyl)amino, amino lower alkyl,mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide”encompasses mercapto, mercapto alkyl and alkylthio, while the termdisulfide encompasses alkyldithio. These preferred substituents may besubstituted on any one of R₁, R₂, R₃, R₄, R₅ or R₆, R₇ or R₈ as definedherein.

[0055] The ZY groups representative of R₂ and R₃ include hydroxy,alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy,such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino;alkylamino, such as methylamino, ethylamino; arylamino, such as anilino;lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt,hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino,N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino,aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino(—NH—OH), lower alkoxy amino [(NHOR₁₈) wherein R₁₈ is lower alkyl],N-lower alkylhydroxyl amino [(NR₁₈)OH wherein R₁₈ is lower alkyl],N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂);alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino,(e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamino.

[0056] The preferred heterocyclic groups representative of R₂ and R₃ aremonocyclic heterocyclic moieties the formula:

[0057] or those corresponding partially or fully saturated form thereofwherein n is 0 or 1; and

[0058] R₅₀ is H or an electron withdrawing group or electron donatinggroup;

[0059] A, Z, L and J are independently CH, or a heteroatom selected fromthe group consisting of N, O, S; and

[0060] G is CH, or a heteroatom selected from the group consisting of N,O and S,

[0061] but when n is O, G is CH, or a heteroatom selected from the groupconsisting of NH, O and S with the proviso that at most two of A, E, L,J and G are heteroatoms.

[0062] When n is 0, the above heteroaromatic moiety is a five memberedring, while if n is 1, the heterocyclic moiety is a six memberedmonocyclic heterocyclic moiety. The preferred heterocyclic moieties arethose aforementioned heterocyclics which are monocyclic.

[0063] If the ring depicted hereinabove contains a nitrogen ring atom,then the N-oxide forms are also contemplated to be within the scope ofthe invention.

[0064] When R₂ or R₃ is a heterocyclic of the above formula, it may bebonded to the main chain by a ring carbon atom. When n is O, R₂ or R₃may additionally be bonded to the main chain by a nitrogen ring atom.

[0065] Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g.,phenyl, aryl alkyl, e.g., benzyl and alkyl.

[0066] It is to be understood that the preferred groups of R₂ and R₃ maybe unsubstituted or substituted with electron donating or electronwithdrawing groups. It is preferred that R₂ and R₃ are independentlyhydrogen, lower alkyl, which is either unsubstituted or substituted withan electron withdrawing group or an electron donating group, such aslower alkoxy (e.g., methoxy, ethoxy, and the like), N-hydroxylamino,N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyl andalkylhydroxyamino.

[0067] It is even more preferred that one of R₂ and R₃ is hydrogen.

[0068] It is preferred that n is one.

[0069] It is preferred that R₂ is hydrogen and R₃ is hydrogen, an alkylgroup which is unsubstituted or substituted by at least an electrondonating or electron withdrawing group or ZY. In this preferredembodiment, it is more preferred that R₃ is hydrogen, an alkyl groupsuch as methyl, which is unsubstituted or substituted by an electrondonating group, or NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ areindependently hydrogen or lower alkyl. It is preferred that the electrondonating group is lower alkoxy, and especially methoxy or ethoxy.

[0070] It is also preferred that R is aryl lower alkyl. The mostpreferred aryl for R is phenyl. The most preferred R group is benzyl. Ina preferred embodiment, the aryl group may be unsubstituted orsubstituted with an electron donating or electron withdrawing group. Ifthe aryl ring in R is substituted, it is most preferred that it issubstituted with an electron withdrawing group, especially on the arylring. The most preferred electron withdrawing group for R is halo,especially fluoro.

[0071] The preferred R₁ is loweralkyl, especially methyl.

[0072] The more preferred compounds are compounds of Formula (I) whereinn is 1; R₂ is hydrogen; R₃ is hydrogen, an alkyl group, especiallymethyl which is substituted by an electron donating or electronwithdrawing group or ZY; R is aryl, aryl lower alkyl, such as benzyl,wherein the aryl group is unsubstituted or substituted and R₁ is loweralkyl. In this embodiment, it is most preferred that R₃ is hydrogen, analkyl group, especially methyl, substituted by electron donating group,such as lower alkoxy, (e.g., methoxy, ethoxy and the like), NR₄OR₅ orONR₄R₇ wherein these groups are defined hereinabove.

[0073] The most preferred compounds utilized are those of the Formula(II):

[0074] wherein

[0075] Ar is aryl, especially phenyl, which is unsubstituted orsubstituted with at least one electron donating group or electronwithdrawing group,

[0076] R₁ is lower alkyl; and

[0077] R₃ is as defined herein, but especially hydrogen, loweralkyl,which is unsubstituted or substituted by at least an electron donatinggroup or electron withdrawing group or ZY. It is even more preferredthat R₃ is, in this embodiment, hydrogen, an alkyl group which isunsubstituted or substituted by an electron donating group, NR₄OR₅ orONR₄R₇. It is most preferred that R₃ is CH₂-Q, wherein Q is loweralkoxy, NR₄OR₅ or ONR₄R₇ wherein R₄ is hydrogen or alkyl containing 1-3carbon atoms, R₅ is hydrogen or alkyl containing 1-3 carbon atoms, andR₇ is hydrogen or alkyl containing 1-3 carbon atoms.

[0078] The preferred R₁ is CH₃. The most preferred R₃ is methoxy.

[0079] The most preferred aryl is phenyl.

[0080] The most preferred compound includes:

[0081] (R)-2-acetamido-N-benzyl-3-methoxy-propionamide,

[0082] O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;

[0083] O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;

[0084] N-acetyl-D-phenylglycine benzylamide;

[0085] D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acidbenzylamide;

[0086] D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acidbenzylamide.

[0087] It is to be understood that the various combinations andpremutations of the Markush groups of R₁, R₂, R₃, R and n describedherein are contemplated to be within the scope of the present invention.Moreover, the present invention also encompasses compounds andcompositions which contain one or more elements of each of the Markushgroupings in R₁, R₂, R₃, n and R and the various combinations thereof.Thus, for example, the present invention contemplates that R₁ may be oneor more of the substituents listed hereinabove in combination with anyand all of the substituents of R₂, R₃, and R with respect to each valueof n.

[0088] The compounds utilized in the present invention may contain one(1) or more asymmetric carbons and may exist in racemic and opticallyactive forms. The configuration around each asymmetric carbon can beeither the D or L form. It is well known in the art that theconfiguration around a chiral carbon atoms can also be described as R orS in the Cahn-Prelog-Ingold nomenclature system. All of the variousconfigurations around each asymmetric carbon, including the variousenantiomers and diastereomers as well as racemic mixtures and mixturesof enantiomers, diastereomers or both are contemplated by the presentinvention.

[0089] In the principal chain, there exists asymmetry at the carbon atomto which the groups R₂ and R₃ are attached. When n is 1, the compoundsof the present invention is of the formula

[0090] wherein R, R₁, R₂, R₃, R₄, R₅, R₆, Z and Y are as definedpreviously.

[0091] As used herein, the term configuration shall refer to theconfiguration around the carbon atom to which R₂ and R₃ are attached,even though other chiral centers may be present in the molecule.Therefore, when referring to a particular configuration, such as D or L,it is to be understood to mean the D or L stereoisomer at the carbonatom to which R₂ and R₃ are attached. However, it also includes allpossible enantiomers and diastereomers at other chiral centers, if any,present in the compound.

[0092] The compounds of the present invention are directed to all theoptical isomers, i.e., the compounds of the present invention are eitherthe L-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂and R₃ are attached). These stereoisomers may be found in mixtures ofthe L and D stereoisomer, e.g., racemic mixtures. The D stereoisomer ispreferred.

[0093] Depending upon the substituents, the present compounds may formaddition salts as well. All of these forms are contemplated to be withinthe scope of this invention including mixtures of the stereoisomericforms

[0094] The preparation of the utilized compounds are described in U.S.Pat. Nos. 5,378,729 and 5,773.475, the contents of both of which areincorporated by reference.

[0095] The compounds utilized in the present invention are useful assuch as depicted in the Formula I or can be employed in the form ofsalts in view of its basic nature by the presence of the free aminogroup. Thus, the compounds of Formula I forms salts with a wide varietyof acids, inorganic and organic, including pharmaceutically acceptableacids. The salts with therapeutically acceptable acids are of courseuseful in the preparation of formulation where enhanced water solubilityis most advantageous.

[0096] These pharmaceutically acceptable salts have also therapeuticefficacy. These salts include salts of inorganic acids such ashydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric,nitric acid and sulfuric acids as well as salts of organic acids, suchas tartaric, acetic, citric, malic, benzoic, perchloric, glycolic,gluconic, succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids,benzenesulfonic), phosphoric, malonic, and the like.

[0097] It is preferred that the compound utilized in the presentinvention is used in therapeutically effective amounts.

[0098] The physician will determine the dosage of the presenttherapeutic agents which will be most suitable and it will vary with theform of administration and the particular compound chosen, andfurthermore, it will vary with the patient under treatment, the age ofthe patient, the type of malady being treated. He will generally wish toinitiate treatment with small dosages substantially less than theoptimum dose of the compound and increase the dosage by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally to found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. The compounds areuseful in the same manner as comparable therapeutic agents and thedosage level is of the same order of magnitude as is generally employedwith these other therapeutic agents.

[0099] In a preferred embodiment, the compounds utilized areadministered in amounts ranging from about 1 mg to about 100 mg perkilogram of body weight per day. This dosage regimen may be adjusted bythe physician to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. The compounds of Formula I may be administered in aconvenient manner, such as by oral, intravenous (where water soluble),intramuscular or subcutaneous routes.

[0100] The compounds of Formula (I) may be orally administered, forexample, with an inert diluent or with an assimilable edible carrier, orit may be enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly into thefool of the diet. For oral therapeutic administration, the activecompound of Formula I may be incorporated with excipients and used inthe form of ingestible tablets, buccal tablets, troches, capsules,elixirs, suspensions, syrups, wafers, and the like. Such compositionsand preparations should contain at least 1% of active compound ofFormula I. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 5 to about 80%of the weight of the unit. The amount of active compound of Formula I insuch therapeutically useful compositions is such that a suitable dosagewill be obtained. Preferred compositions or preparations according tothe present invention contains between about 10 mg and 6 g activecompound of Formula I.

[0101] The tablets, troches, pills, capsules and the like may alsocontain the following: A binder such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, lactose or saccharin may be added or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier.

[0102] Various other materials may be present as coatings or otherwisemodify the physical form of the dosage unit. For instance, tablets,pills, or capsules may be coated with shellac, sugar or both. A syrup orelixir may contain the active compound, sucrose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and formulations.For example, sustained release dosage forms are contemplated wherein theactive ingredient is bound to an ion exchange resin which, optionally,can be coated with a diffusion barrier coating to modify the releaseproperties of the resin.

[0103] The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquid,polyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

[0104] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases the form must be sterile and mustbe fluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

[0105] Sterile injectable solutions are prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying the freeze-dryingtechnique plus any additional desired ingredient from previouslysterile-filtered solution thereof.

[0106] As used herein, “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agent, isotonic and absorption delaying agents forpharmaceutical active substances as well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions.

[0107] It is especially advantageous to formulate parenteralcompositions in dosage unit form or ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the mammaliansubjects to be treated; each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specifics forthe novel dosage unit forms of the invention are dictated by anddirectly dependent on (a) the unique characteristics of the activematerial an the particular therapeutic effect to be achieved, and (b)the limitations inherent in the art of compounding such as activematerial for the treatment of disease in living subjects having adiseased condition in which bodily health is impaired as hereindisclosed in detail.

[0108] The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedescribed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 10 mg to about 6 g.Expressed in proportions, the active compound is generally present infrom about 1 to about 750 mg/ml of carrier. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients.

[0109] As used herein the term “patient” or “subject” refers to a warmblooded animal, and preferably mammals, such as, for example, cats,dogs, horses, cows, pigs, mice, rats and primates, including humans. Thepreferred patient is humans.

[0110] The term “treat” refers to either relieving the pain associatedwith a disease or condition or alleviating the patient's disease orcondition.

[0111] The compounds of the present invention are useful for treatingchronic pain. As used herein, the term “chronic pain” is defined as painpersisting for an extended period of time, for example, greater thanthree to six months, although the characteristic signs describedhereinbelow can occur earlier or later than this period. Vegetativesigns, such as lassitude, sleep disturbances, decreased appetite, loseof taste or food, weight loss, diminished libido and constipationdevelop.

[0112] Types of pain that the compounds of the present invention areespecially useful in treating are is acute and chronic pain,particularly non neuropathic inflammatory pain. This include chronicinflammatory pain, e.g. rheumatoid arthritis pain and/or secondaryinflammatory osteoarthritic pain.

[0113] The compounds of the present invention are administered to apatient suffering from the aforementioned type of pain in an analgesiceffective amount. These amounts are equivalent to the therapeuticallyeffective amounts described hereinabove.

[0114] The following working examples show the antinociceptiveproperties in well-defined animal models of acute and chronic pain.

[0115] The used substance was SPM 927 which is the synonym forHarkoseride. The standard chemical nomenclature is(R)-2-acetamide-N-benzyl-3-methoxypropionamide.

1. EXAMPLE 1

[0116] Formalin Test, Rat

[0117] Prolonged Inflammatory Pain

[0118] Significant and dose dependent efficacy of SPM 927 could bedemonstrated in the late phase of the rat formalin test.

[0119] The formalin test is a chemically-induced tonic pain model inwhich biphasic changes of nociceptive behaviour are assessed andspinal/supraspinal plasticity of nociception is considered as amolecular basis for neuropathic pain particularly during the second(=late) phase of the test, during which most clinically used drugsagainst neuropathic pain are active. These features have resulted in theformalin test being accepted as a valid model of persistent clinicalpain.

[0120] The compound was tested for anti-nociceptive properties by use ofthe weighted behavioural scoring method: Freely moving animals underwentobservational assessment of the position of the left hind paw accordingto a rating score scaled 0-3 before and 10, 20, 30 and 40 min afterinjection of 0.05 ml of sterile 2.5% formalin under the skin on thedorsal surface of the paw. SPM 927, administered i.p. just prior toformalin injection produced dose dependant reduction of theformalin-induced tonic inflammatory nociceptive behaviour as shown intable 1 (weighted pain scores±SEM, n=11-12/group). TABLE 1 Weighted painscore, formalin test, rat Dose No.of Time After Injection of formalinand SPM 927 [mg/kg] Animals BASELINE 10 MIN 20 MIN 30 MIN 40 MIN 0 110.00 ± 0.00 0.30 ± 0.16 0.93 ± 0.21 1.84 ± 0.19  2.10 ± 0.24  5 12 0.01± 0.01 0.31 ± 0.11 0.78 ± 0.23 1.47 ± 0.20  1.46 ± 0.19* 10 11 0.00 ±0.00 0.42 ± 0.17  0.33 ± 0.16* 1.02 ± 0.27* 1.05 ± 0.19* 20 12 0.00 ±0.00 0.48 ± 0.18 0.57 ± 0.14 0.78 ± 0.18* 1.02 ± 0.24* 40 12 0.00 ± 0.000.12 ± 0.05  0.10 ± 0.04* 0.09 ± 0.06* 0.12 ± 0.06*

[0121] The term ANOVA stands for Analysis of Variance.

2. EXAMPLE 2

[0122] Chronic Constriction Injury (CCI, Bennett-Model)

[0123] The effectiveness of SPM 927 in reducing spontaneous chronicpain, mechanical allodynia, and thermal hyperalgesia was tested usingthe chronic constriction injury (CCI) model of peripheral neuropathy,one of the best characterised in vivo animal models used to studychronic pain due to peripheral nerve injury. In this model, looseligatures are placed around the sciatic nerve, which produces axonalswelling and a partial deafferentation manifested as a significant butincomplete loss of axons in the distal portion of the peripheral nerve.One of the prominent behaviours seen following sciatic nerve ligation isthe appearance of hind paw guarding, thought to be an indication of anongoing spontaneous chronic pain. Support for this idea is derived fromreports of increased spinal cord neural activity, and increasedspontaneous neuronal discharge in spinothalamic tract neurons and in theventrobasal thalamus in the absence of overt peripheral stimulation. Inaddition to the appearance of spontaneous pain behaviours, severalabnormalities in stimulus evoked pain occur as a result of CCI,including thermal hyperalgesia and mechanical allodynia. The developmentof these abnormal stimulus-evoked pains has also been reported asoccurring in areas outside the territory of the damaged nerve, areasinnervated by uninjured nerves.

[0124] Behavioural tests for thermal hyperalgesia, and mechanicalallodynia were conducted to evaluate different components of neuropathicpain. Baseline data for each test was collected prior to anyexperimental procedure; in addition, all animals were tested for thedevelopment of chronic pain behaviours 13-25 days after CCI surgery 1day prior to the day of vehicle (0.04 ml sterile water/10 g body weight)or drug administration and after vehicle/drug administration. Thesequence of the tests was pain-related behaviour (1) thermalhyperalgesia, (2) mechanical allodynia in order to minimise theinfluence of one test on the result of the next. The testing proceduresand results are presented separately for each aspect of chronic pain.Either 0 (vehicle, 0.04 ml/10 g body weight), 5, 10, 20 or 40 mg/kg ofSPM 927 (n=7-23/group) was administered i.p. 15 minutes before the firstbehavioural test.

[0125] (1) Thermal hyperalgesia was assessed by means of withdrawallatency in response to radiant heat applied to the subplantar surface ofthe ligated rat hind paw according to Hargreaves. As compared to thebaseline latency (s), a significant decrease in the (postoperative)latency of foot withdrawal in response to the thermal stimulus wasinterpreted as indicating the presence of thermal hyperalgesia followingchronic constriction injury.

[0126] SPM 927 dose dependently reduced chronic constrictioninjury-induced thermal hyperalgesia as shown in table 2 [latencies(s)±SEM]. Significant effects were observed only at the highest dosestested (20 and 40 mg/kg i.p.) with the maximum effect seen already at 20mg/kg i.p. TABLE 2 Thermal hyperalgesia, CCI model, rat Post- Dose No.of Post- operative + [mg/kg] Animals Baseline operative SPM 927 0 13 9.7 ± 0.73 6.9 ± 0.28  7.3 ± 0.42 5 7 10.5 ± 0.68 8.1 ± 0.59  9.1 ±0.97 10 7  9.2 ± 0.68 7.0 ± 0.60  8.0 ± 0.58 20 8  9.9 ± 0.69 6.9 ± 0.56 9.7 ± 0.95* 40 8  8.3 ± 0.57 7.4 ± 0.47 10.2 ± 0.77*

[0127] Mechanical sensitivity and allodynia of the ligated rat hind pawwas quantified by brisk foot withdrawal in response to normallyinnocuous mechanical stimuli as described previously. Responsiveness tomechanical stimuli was tested with a calibrated electronic Von Freypressure algometer connected to an online computerised data collectionsystem. A significant decrease in the post operative compared tobaseline pressure (g/mm²) necessary to elicit a brisk foot withdrawal inresponse to this mechanical stimulus is interpreted as mechanicalallodynia.

[0128] (2) SPM 927 dose dependently reduced the intensity of mechanicalallodynia induced by unilateral nerve ligation as shown in table 3[pressure (g/mm²)±SEM]. Regression analysis showed a positive linearcorrelation between the dose of SPM 927 and the increase in the amountof force required to produce foot withdrawal. TABLE 3 Mechanicalallodynia, CCI model, rat Post- Dose No. of Post- operative + [mg/kg]Animals Baseline operative SPM 927 0 20 41.6 ± 2.20 18.7 ± 2.08 20.2 ±1.89 5 11 53.6 ± 3.34 16.4 ± 2.56 21.8 ± 2.33 10 17 42.9 ± 2.54 21.1 ±2.12 29.2 ± 2.84* 20 8 46.0 ± 2.62 24.6 ± 2.78 39.5 ± 3.62* 40 9 48.3 ±3.83 23.8 ± 2.23 42.9 ± 5.47*

3. EXAMPLE 3

[0129] Randall-Selitto Paw Pressure Test, Rat

[0130] Further potential anti-nociceptive efficacy of SPM 927 wasassessed in a rat experimental model of acute inflammation using amodified Randall and Selitto. procedure. Acute inflammation is inducedby injection of s.c. carrageenen (1.0 mg in 0.1 ml saline/paw), anunspecific inflammatory agent, into the plantar surface of one hind pawof the animal. Mechanical sensitivity and nociceptive thresholds weremeasured using an algesimeter device that exerts a constantly increasingmechanical force (10 mm Hg/sec) on the inflammed hind paw. Themechanical nociceptive threshold is defined as the pressure (mm Hg) atwhich the rat vocalises or struggles or withdraws its paw. Since itsoriginal description, the Randall and Selitto mechanical paw pressuretest has become a standard method for testing the efficacy of newcompounds for alleviating acute inflammatory pain.

[0131] SPM 927 or vehicle (sterile water, 0.04 ml/log body weight) wasadministered i.p 1 hr and 45 minutes after carrageenen, meaning 15 to 20minutes before the start of behavioural testing. As compared to theresponse threshold of vehicle-treated controls, an increase in thepressure required to produce a behavioural response is interpreted asantinociception. SPM 927 at 20 and 40 mg/kg i.p. significantly increasedthe pressure required to elicit a paw withdrawal during acutecarrageenen induced inflammation in the Randall-Sellito paw pressuretest, indicating a reduction of mechanical hyeralgesia as shown in table4 [pressure (mm Hg)±SEM, n=12/group]. TABLE 4 Mechanical hyperalgesia,modified Randall-Selitto, rat Dose [mg/ Carrageenen + kg] BaselineCarrageenen alone SPM 927 0 101.5238 ± 14,9666 40.85714 ± 9.319 45.07143± 5.569 20 142.5694 ± 12.834  108.222 ± 10.180 164.7639 ± 13.533* 40164.8889 ± 18.360  89.963 ± 7.457  232.741 ± 22.034*.

[0132] Due to high variation of baseline responses and mechanicalhyperalgesia following carrageenen injection, a direct comparison of theabsolute paw pressures required to elicit a behavioural response isinappropriate. However, vehicle (0 mg /kg, sterile water, 0.04 ml/10 gbody weight) had little effect on behavioural responsiveness, but SPM927 at doses of 20 and 40 mg/kg i.p. markedly reduced the mechanicalhyperalgesia induced by carrageenen.

[0133] Test Results

[0134] Harkoseride proved to be anti-nociceptive in several differentexperimental animal models that reflect different types and symptoms ofpain. The prolonged inflammatory nociception produced in the ratformalin test and mechanical allodynia in the rat CCI model appearedmost sensitive to the effects of SPM 927, showing significant dosedependent reductions in nociceptive behaviour measurements, even at the10 mg/kg i.p. dose. In addition, but at higher doses SPM 927 exhibitedstatistically significant reduction in pain on other types ofnociception, thermal hyperalgesia (paw flick Hargreaves test, rat CCImodel), and mechanical hyperalgesia due to acute inflammation (modifiedrat Randall-Selitto test).

[0135] Thus, the anti-nociceptive profile of SPM 927 differs fromclassical analgesics like opioids and the standard anti-inflammatorydrugs of the NSAID-type (non-steroidal anti-inflammatory drug),furthermore and surprisingly, the antinociceptive profiling obtained anddescribed by the data given table 1-4 is even different to otheranticonvulsant drugs used for pain relief.

[0136] The weak but not significant effects on thermal and mechanicalhyperalgesia led to the following investigation:

4. EXAMPLE 4

[0137] Antinociceptive Effects of Harkoseride in an Animal Model forRheumatoid Arthritis

[0138] In the following study harkoseride is hereinafter referred to asSPM 927.

[0139] Method:

[0140] Experiments were performed in female Wistar rats weighing 80-90 gat the beginning of the experiments. Arthritis was induced byintraplantar injection of Freund's complete adjuvans (FCA, 0.1 ml) toone hindpaw. Drugs were given on day 11 after FCA injection in animalswhich developed systemic secondary arthritic symptoms as assessed byvisual inspection. Mechanical hyperalgesia was than acutely applied andmeasured by means of the paw pressure test (Randall Selitto method) andsupraspinal vocalisation as the biological endpoint of the nociceptivereaction. Measurements were taken at 0 min (before drug injection) and15 min, 30 min, 60 min, and 24 h after drug injection and all data areexpressed as percent of maximal possible effect (% MPE).

[0141] 10 groups of 15 rats were used and received the followingtreatments: drug [dose in No. FCA mg/kg]/time comment 1 no no healthycontrols 2 yes no arthritic controls 3 yes SPM 927 [5] acute treatmentgroup (anti-nociceptive effects) 4 yes SPM 927 [10] acute treatmentgroup (anti-nociceptive effects) 5 yes SPM 927 [20] acute treatmentgroup (anti-nociceptive effects) 6 yes SPM 927 [30] acute treatmentgroup (anti-nociceptive effects 7 yes SPM 927 [40] acute treatment group(anti-nociceptive effects) 8 yes SPM 927 [30] early treatment group(anti-inflammatory (with FCA) effects) 9 no morphine [10] positivecontrol group (normal condition) 10 yes morphine [10] positive controlgroup (disease condition)

[0142] Results: % MPE group # treatment 15 min 30 min 60 min 24 h 1Control −5 −2 +2 −5 2 FCA/VEH +12 +2 0 +3 3 FCA/SPM 5 −5 −5 −12 −14 4FCA/SPM 10 +7 −2 0 −5 5 FCA/SPM 20 +1 −20 −9 −20 6 FCA/SPM 30 +58 +33+16 −8 7 FCA/SPM 40 +100 +100 +14 −7 8 FCA/SPM 30 −14 −7 −3 −11 (early)9 MOR 10 +100 +100 +100 +2 10 FCA/MOR10 +100 +100 +100 −7

[0143] SPM 927 showed dose-dependent anti-nociceptive but noanti-inflammatory effects. The anti-nociceptive effects started at adose of 30 mg/kg and were most prominent during the first 30 min oftesting. Morphine, as a positive control substance had clearantinociceptive effects in arthritic and normal animals.

[0144] Conclusion:

[0145] Surprisingly and unexpected SPM 927 shows dose-dependentantinociceptive effects in rats that suffer from Freund's completeadjuvans induced arthritis (significant so at doses of 30 and 40 mg/kg).This antinociception is not caused by potential anti-inflammatoryeffects. Under this chronic inflammatory pain condition theantinociceptive effect of SPM 927 (see FIG. 1) showed full intrinsicactivity and suggests SPM 927 to be effective in rheumatoid arthriticpain as well as secondary inflammatory osteoarthritis.

1. Use of a compound having the Formula (I)

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; R₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; and wherein heterocyclic in R₂ and R₃ is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; Z is O, S, S(O)₂, NR₆′; or PR₄; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

R₆′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R₄ may be unsubstituted or substituted with an electron withdrawing group or electron donating group; R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and R₇ is COOR₈, COR₈, hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R₇ may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and n is 1-4; and a is 1-3, or of a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain in mammals.
 2. Use of a compound according to claim 1 wherein one of R₂ and R₃ is hydrogen.
 3. Use of a compound according to claim 1 wherein n is
 1. 4. Use of a compound according to claim 1 wherein one of R₂ and R₃ is hydrogen and n is
 1. 5. Use of a compound according to claim 1 wherein R is aryl lower alkyl and R₁ is lower alkyl.
 6. Use of a compound according to claim 1 wherein R₂ and R₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl or ZY is NR₅R₆R₇, NR₅OR₆, ONR₅R₇,


7. Use of a compound according to claim 4 wherein R₂ and R₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZY is NR₅NR₆R₇, NR₅OR₆, ONR₅R₇,


8. Use of a compound according to claim 4 wherein R₂ is hydrogen and R₃ is lower alkyl, which may be unsubstituted with an electron donating or electron withdrawing group, NR₄OR₅, or ONR₄R₇.
 9. Use of a compound according to claim 4 wherein R₃ is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR₄OR₆ or ONR₄R₇, wherein R₅ and R₇ are independently hydrogen or lower alkyl, R is aryl loweralkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R₁ is lower alkyl,
 10. Use of a compound according to claim 9 wherein aryl is phenyl.
 11. Use of a compound according to claim 9 wherein aryl is phenyl and is unsubstituted or substituted with halo.
 12. Use of a compound according to claim 1 wherein the compound is (R)-2-acetamide-N-benzyl-3-methoxy-propionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide; D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.
 13. Use of a compound according to claim 1 wherein the pain is non neuropathic inflammatory pain.
 14. Use of a compound according to claim 9 wherein the pain is non neuropathic inflammatory pain.
 15. Use of a compound according to claim 1 wherein the pain is acute pain.
 16. Use of a compound according to claim 1 wherein the pain is chronic pain.
 17. Use of a compound according to claim 1 wherein the pain is chronic inflammatory pain.
 18. Use of a compound according to claim 1 wherein the pain is rheumatoid arthritis pain.
 19. Use of a compound according to claim 1 wherein the pain is secondary inflammatory osteoarthritic pain.
 20. Use of a compound according to claim 1 wherein the pain is not nociceptive pain.
 21. Use of a compound having the Formula (II)

wherein Ar is phenyl which is unsubstituted or substituted with at least one halo group; R₃ is lower alkoxy containing 1-3 carbon atoms and R₁ is lower alkyl containing 1-3 carbon atoms or of a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of acute and chronic pain, especially non neuropathic inflammatory pain.
 22. Use of a compound according to claim 21 wherein Ar is unsubstituted phenyl for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 23. Use of a compound according to claims 21 and 22 wherein halo is fluoro for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 24. Use of a compound according to claims 21-23 wherein R₃ is alkoxy containing 1-3 carbon atoms and Ar is unsubstituted phenyl for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 25. Use of a compound in the R configuration having the formula

wherein Ar is phenyl which is unsubstituted or substituted with at least one halo group; R₃ is lower alkoxy containing 1-3 carbon atoms and R₁ is methyl or of a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 26. Use of the compound according to claim 25 which is substantially enantiopure for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 27. Use of a compound according to claims 25 and 26 wherein Ar is unsubstituted phenyl for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 28. Use of a compound according to claims 25-27 wherein halo is fluoro for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 29. Use of a compound according to claims 25-28 wherein R₃ is alkoxy containing 1-3 carbon atoms and Ar is unsubstituted phenyl for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain.
 30. Use of (R)-2-Acetamido-N-benzyl-3-methoxypropionamide or its pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain in mammals.
 31. Use of (R)-2-Acetamide-N-benzyl-3-methoxy-propionamide or its pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of chronic inflammatory pain in mammals.
 32. Use of the compound or its pharmaceutically acceptable salt thereof according to claim 31 for the treatment of rheumatoid arthritis pain.
 33. Use of the compound or its pharmaceutically acceptable salt thereof according to claim 31 for the treatment of secondary inflammatory osteoarthritic pain.
 34. Use of the compound according to claims 30-33 which is substantially enantiopure for the preparation of a pharmaceutical composition for the treatment of non neuropathic inflammatory pain in mammals.
 35. A pharmaceutical composition comprising a non neuropathic inflammatory pain effective amount of a compound according to any one of claims 1-28 and a pharmaceutical carrier thereof. 